Apparatus and method for aerosol delivery to the lungs or other locations of the body

ABSTRACT

This disclosure relates to an apparatus useful for the delivery of aerosols, such as those containing drugs, to the lungs or other locations in the body. The disclosure also relates to methods of administering an aerosol to the lungs or other locations in the body of a patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/720,341, filed March 9, 2010, the entire contents of which is fullyincorporated herein by reference.

TECHNICAL FIELD

This disclosure relates to an apparatus useful for the delivery ofaerosols, such as those containing pharmaceutically and/or biologicallyactive agents (e.g., drugs), to the lungs or other locations in thebody. The disclosure also relates to methods of using the disclosedapparatus for administering an aerosol to the lungs or other locationsin the body of a patient.

BACKGROUND

Aerosols represent an important delivery form for the administration ofpharmaceutically active agents to patients. Typically, aerosols arehomogenous colloidal mixtures that comprise a dispersed phase and acontinuous, gaseous medium.

One example of an aerosol is a liquid aerosol in which the dispersedphase is a liquid and the continuous medium is a gas. Liquid aerosolsare an important delivery form for the administration ofpharmaceutically active agents to patients. Liquid aerosols can be usedto deliver diverse categories of pharmaceutically active agents. Thesepharmaceutically active agents can include small molecules such ascancer treating chemotherapeutic agents, peptide chains such astherapeutic antibodies or vaccine antigens and nucleic acids, such asDNA or siRNA, for gene therapy.

Epithelial tissue lining the lungs, as well as other organs and bodycavities, is a very important target tissue for the delivery ofpharmaceutical compositions to patients. In fact, the delivery ofaerosols to different parts of the respiratory tract, such as theairways and alveoli, may be used to treat a variety of differentconditions. These conditions include lung cancer, asthma, bronchitis,bronchiectasis, pneumonia, infectious diseases, tuberculosis, influenza,inflammatory disease, chronic obstructive pulmonary disease, cysticfibrosis, respiratory distress syndrome, Parkinson's disease, diabetes,osteoporosis and systemic diseases such as cardiopulmonary hypertension.The targeted delivery of aerosols containing pharmaceutically activeagents also helps avoid side effects associated with the oral, orparenteral, administration of some pharmaceutically active agents.

A significant limitation in the use of aerosols in treating patients hasbeen that only small volumes of aerosols can be delivered to targettissues, such as the lungs, using existing technologies. Aerosolsgenerated by jet, thermal, or ultrasonic methods and delivered byinhalation are relatively slow, highly inefficient and imprecise. Theydepend upon the ability of the patient to respire a clinically effectivedose, that is being directed at the patient's nose and mouth at highspeed in relatively low concentrations. If the patient is a newborn withimpaired respiratory function, is unconscious or is too physicallyimpaired by disease, the ability to achieve a sufficient concentrationin the lungs may not be feasible by inhalation alone. This can haveadditional consequences. For example, if antibiotics are administered asinhaled therapies via a nebulizer in insufficient concentrations tofully overcome the disease, this may expose the patient to greaterlikelihood of antibiotic resistance. Aerosol generating methods thatdepend on compressed air or propellants to generate particles in the 1-5micron size range which are small enough to be respirable by the patientfrom outside the body are typically moving at high momentum which canforce as much as 95% of the dose against the back of the throat, whereit may be coughed up or swallowed. Current inhalation therapies do notpermit targeted local/regional drug administration to a lobe or lesionwithin the lung. They do not protect the nose, mouth, throat, trachea orother sensitive tissues in the respiratory tract from exposure to drugsthat may be hazardous or harmful to healthy tissue if respired, such asaerosolized chemotherapy. The small particles size produced byinhalation therapy methods are also more likely to be exhaled by thepatient, contaminating the environment and creating potential hazardsfor caregivers. In addition, these technologies that depend on heat, orpropellants, can affect the efficacy and viability of many therapeuticformulations and alter the pharmaceutically and/or biologically activeagents that are being delivered. Such inhalation technologies are alsoincompatible with the administration of drugs in aerosol form to manyother target tissues and organs.

Thus, a need exists for apparatuses and methods that may be used toadminister efficiently and precisely deliver aerosols to target tissues,and organs, such as the lungs.

SUMMARY

We provide an apparatus comprising a reservoir in fluid communicationwith an outlet channel; a low pressure pump inlet in fluid communicationwith the outlet channel; a high pressure pump in fluid communicationwith the low pressure pump inlet; a high pressure pump outlet in fluidcommunication with the high pressure pump; a switching valve in fluidcommunication with the high pressure pump outlet, said switching valvehaving a delivery outlet and a release outlet; an aerosolizer in fluidcommunication with the delivery outlet; and a restrictor in fluidcommunication with the release outlet.

One aspect of the disclosure is an apparatus comprising a reservoir influid communication with an outlet channel; a low pressure pump inlet influid communication with the outlet channel; a high pressure pump influid communication with the low pressure pump inlet; a high pressurepump outlet in fluid communication with the high pressure pump; aswitching valve in fluid communication with the high pressure pumpoutlet, said switching valve having a delivery outlet and a releaseoutlet; an aerosolizer in fluid communication with the delivery outlet;and a restrictor in fluid communication with the release outlet.

Another aspect of the disclosure is an apparatus comprising a reservoirin fluid communication with an outlet channel; a low pressure pump inletin fluid communication with the outlet channel; a high pressure pump influid communication with the low pressure pump inlet; a high pressurepump outlet in fluid communication with the high pressure pump; aswitching valve in fluid communication with the high pressure pumpoutlet, said switching valve containing a fluid at high pressure andhaving a delivery outlet and a release outlet; a controller connected tothe switching valve; a flexible connector in fluid communication withthe delivery outlet; an aerosolizer in fluid communication with theflexible connector; and a restrictor in fluid communication with therelease outlet.

Another aspect of the disclosure is an apparatus comprising a reservoirin fluid communication with an outlet channel; a low pressure pump inletin fluid communication with the outlet channel; a high pressure pump influid communication with the low pressure pump inlet; a high pressurepump outlet in fluid communication with the high pressure pump; and anaerosolizer in fluid communication with the high pressure pump outlet.

Another aspect of the disclosure is an apparatus comprising a reservoirin fluid communication with an outlet channel; a low pressure pump inletin fluid communication with the outlet channel; a high pressure pump influid communication with the low pressure pump inlet; a high pressurepump outlet in fluid communication with the high pressure pump; acontroller connected to the high pressure pump; a flexible connector influid communication with the high pressure pump outlet; and anaerosolizer in fluid communication with the flexible connector.

Another aspect of the disclosure is an apparatus comprising a reservoirin fluid communication with an outlet channel; a low pressure pump inletin fluid communication with the outlet channel; a high pressure pump influid communication with the low pressure pump inlet, a high pressurepump outlet in fluid communication with the high pressure pump; aswitching valve in fluid communication with the high pressure pumpoutlet, said switching valve containing a fluid at high pressure andhaving a delivery outlet and a release outlet; a controller connected tothe switching valve; a flexible connector in fluid communication withthe delivery outlet; an aerosolizer in fluid communication with theflexible connector; and a restrictor in fluid communication with therelease outlet.

Another aspect of the disclosure is a method of administering an aerosolto a patient comprising providing an apparatus of the disclosure;placing the aerosolizer adjacent to a target tissue in a patient; andoperating the apparatus to produce an aerosol; whereby an aerosol isadministered to the patient.

Another aspect of the disclosure is a method of administering achemotherapeutic aerosol to the lungs of a patient comprising providingthe apparatus of the disclosure in which the reservoir contains achemotherapeutic agent placing the aerosolizer adjacent to a targettissue in the lungs of a patient; and operating the apparatus to producea chemotherapeutic aerosol; whereby a chemotherapeutic aerosol isadministered to the lungs of the patient.

Another aspect of the disclosure is an apparatus comprising a reservoirin fluid communication with a pressure generator; a flexible connectionin fluid communication with the pressure generator; and an aerosolizerin fluid communication with the pressure generator.

The disclosure also provides methods of administering an aerosol to apatient by operating the disclosed apparatus to produce an aerosol.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows, from a frontal perspective, one embodiment of an apparatusof the disclosure.

FIG. 2 shows, from a frontal perspective, one example of a switchingvalve of an apparatus of the disclosure.

FIG. 3 shows, from a side perspective, an exploded view of one exampleof an aerosolizer of an apparatus of the disclosure.

FIG. 4 shows, from a side perspective, a cut away view of one example ofan aerosolizer of an apparatus of the disclosure.

FIG. 5 shows, from a frontal perspective, one embodiment of an apparatusof the disclosure.

FIG. 6 shows, from a side perspective, one embodiment of a controller ofan apparatus of the disclosure.

FIG. 7 shows, from a side perspective, one embodiment of a controller ofan apparatus of the disclosure.

FIG. 8 shows, from a side perspective, one embodiment of a controller ofan apparatus of the disclosure.

FIG. 9 shows, from a side perspective, one embodiment of a controller ofan apparatus of the disclosure.

FIG. 10 shows, from a side perspective, a cross-section through a longaxis of one embodiment of a controller of an apparatus of thedisclosure.

FIG. 11 shows, from a side perspective, one embodiment of a reservoir ofan apparatus of the disclosure.

FIG. 12 shows, from a side perspective, a cross-section through oneembodiment of a reservoir of an apparatus of the disclosure.

FIG. 13 shows, from a frontal perspective, one embodiment of anapparatus of the disclosure.

DETAILED DESCRIPTION

It will be appreciated that the following description is intended toprovide details concerning specific representative aspects of thedisclosure. It will also be appreciated that a wide variety ofequivalents may be substituted for the specified elements of the methodsdescribed herein without departing from the spirit and scope of thisdisclosure as described in the appended claims. Additionally, allpublications, including but not limited to patents and patentapplications, cited in this disclosure are herein incorporated byreference as though fully set forth. Ranges identified herein areintended to include the values defining the upper and lower limits of arecited range, all discrete values within the range and any discretesub-range within the range.

The term “reservoir” as used herein includes any container able to holda volume of a fluid. A reservoir may be a vessel of any configurationsuch as, for example, a syringe, bottle, bladder, jar, vial or canister.A reservoir may also be sealed and enclose an interior space that is,partially or completely, inaccessible to the surrounding externalenvironment.

The term “fluid” as used herein includes any substance that continuallydeforms, or flows, under an applied shear stress. A fluid may comprise agas or liquid and may also contain solids (e.g., slurries, suspensions,etc.).

The term “fluid communication” as used herein means that fluid can betransferred, either directly or indirectly, between at least twocomponents of an apparatus. This term also describes a physicalrelationship between components. For example, a first component may beplaced in fluid communication with a second component by a connectingconduit, such as a pipe joining each component so that a volume of fluidcan be transferred from the first component to the second component orvice versa.

The term “outlet channel” as used herein includes any opening in areservoir through which a fluid can be transferred, directly orindirectly, to a low pressure pump inlet.

The term “low pressure pump inlet” as used herein includes any openingon a high pressure pump through which a fluid, at a pressure lower thanthe fluid pressure generated by the pump, can be transferred, directlyor indirectly, to the high pressure pump.

The term “high pressure pump” as used herein includes any device able tomove a fluid and to produce a fluid exerting a pressure of at leastabout 300 pounds per square inch. Examples of high pressure pumpsinclude direct lift, displacement, velocity, buoyancy and gravity pumps.High pressure pumps can also produce fluids exerting pressures of atleast about 400 pounds per square inch, of at least about 2,500 poundsper square inch, of at least about 3,000 pounds per square inch, of atleast about 3,500 pounds per square inch, of at least about 6,000 poundsper square inch, of at least about 15,000 pounds per square inch, of atleast about 20,000 pounds per square inch, and of at least about 300pounds per square inch to about 20,000 pounds per square inch or more.

The term “high pressure pump outlet” as used herein includes any openingon a high pressure pump through which a fluid can be transferred,directly or indirectly, to a switching valve or an aerosolizer.

The term “pressure generator” as used herein includes any structure thatgenerates a pressure differential sufficient to move a fluid.

The term “switching valve” as used herein includes any valve comprisingat least one delivery outlet and at least one release outlet in fluidcommunication with a high pressure pump outlet, so that the valve can beconfigured to transfer a fluid though either a delivery outlet or arelease outlet. A switching valve may also comprise multiple valves thatcan be configured to transfer a fluid through either a delivery outletor a release outlet.

The term “delivery outlet” as used herein includes any opening on aswitching valve through which a fluid can be transferred, directly orindirectly, to an aerosolizer. This means a delivery outlet is in fluidcommunication with an aerosolizer which produces an aerosol to bedelivered.

The term “release outlet” as used herein includes any opening on aswitching valve through which a fluid can be transferred, directly orindirectly, to a restrictor.

The term “aerosolizer” as used herein includes any structure throughwhich a liquid, such as liquid droplets, or a solid, such as aparticulate, is released and entrained in a gas to produce an aerosol inwhich the dispersed phase comprises a liquid, or a solid, and thecontinuous medium comprises a gas. An aerosolizer may comprise anorifice through which liquid droplets are released and entrained in agas to produce a liquid aerosol. An aerosolizer may also comprise anorifice through which a gas passes into a fluid to produce a liquidaerosol. An aerosolizer may comprise an orifice through which solids,such as particulates, are released and entrained in a gas to produce asolid aerosol. An aerosolizer may also comprise an orifice through whicha gas passes into a solid, such as a collection or particulates or afriable substance, to produce a solid aerosol.

The term “restrictor” as used herein includes any structure that has ainlet side, an outlet side and a structure that constrains the flow of afluid to maintain a high pressure fluid on the inlet side and produce alow pressure fluid on the outlet side.

The term “high pressure fluid” as used herein includes withoutlimitation any liquid exerting a pressure of at least about 300 poundsper square inch. A high pressure fluid can also exert pressures of atleast about 400 pounds per square inch, of at least about 2,500 poundsper square inch, of at least about 3,000 pounds per square inch, of atleast about 3,500 pounds per square inch and of at least 300 pounds persquare inch to about 3,500 pounds per square inch.

The term “controller” as used herein includes any device that affectsthe operation of a pump or switching valve and regulates whether theswitching valve is configured to transfer a fluid though either adelivery outlet or a release outlet.

The term “release outlet return” as used herein includes any opening onthe reservoir through which a fluid can be transferred, directly orindirectly, into the reservoir.

The term “target tissue” as used herein includes any aggregate of cellsforming a structure of an animal to which an aerosol is to beadministered.

The term “patient” as used herein includes an animal belonging to anygenus to which administration of an aerosol is indicated. One example ofsuch a subject is a human such as a human patient.

The term “aerosol” as used herein means an aerosol in which thedispersed phase comprises a liquid or solid and the continuous mediumcomprises a gas. A liquid aerosol in which the dispersed phase comprisesa liquid and the continuous medium comprises a gas is one example of anaerosol. A solid aerosol in which the dispersed phase comprises a solid,such as a particulate, and the continuous medium comprises a gas isanother example of an aerosol.

The term “chemotherapeutic agent” as used herein includes pharmaceuticalagents used to treat or prevent cancer.

The term “chemotherapeutic aerosol” as used herein means an aerosolwhich comprises a chemotherapeutic agent.

One aspect of the disclosure is an apparatus comprising a reservoir influid communication with an outlet channel; a low pressure pump inlet influid communication with the outlet channel; a high pressure pump influid communication with the low pressure pump inlet; a high pressurepump outlet in fluid communication with the high pressure pump; aswitching valve in fluid communication with the high pressure pumpoutlet, said switching valve having a delivery outlet and a releaseoutlet; an aerosolizer in fluid communication with the delivery outlet;and a restrictor in fluid communication with the release outlet.

In the apparatus of the disclosure the reservoir may be a syringe, orother vessel such as a canister or flexible bladder, with walls definingan interior space that can contain a fluid that is a liquid or gas. Thereservoir may also comprise a vessel such as a vial containing a fluidsealed with a septum that is placed in fluid communication with anoutlet channel by piercing, or removing, a portion of the septum. Theseptum may comprise any appropriate material such as polymers, alloysand the like, that may be pierced with a piercing structure, such as aneedle, and maintains a seal with the piercing structure such that fluidin the reservoir does not leak past the sides of the piercing structure.For example, the reservoir may be a glass vial having a volume of 20 mLwith a rubber septum affixed to the vial with a metal seal. Those ofordinary skill in the art will recognize other reservoir configurationssuitable for use in the apparatus of the disclosure.

As described above, a vial with a septum may be used as a reservoir.Such a reservoir may be conveniently filled with a fluid sample,sterilized, and stored before the production and administration of anaerosol. Such a vial may have volume graduations, as shown in FIG. 11,so that fluid sample delivery can be monitored. Fluid in the vial can beplaced in fluid communication with the apparatus by holding the vialvertically, then inverting the vial and pushing the vial down onto oneor more needles, or other structures, which form an outlet channel orgas inlet through a septum in the vial. The vial is pushed onto theneedles until the openings of both the inlet and outlet channels areinside the vial and fluid in the vial is able to enter the needleforming the outlet channel. When a pump of the apparatus is activated,fluid is withdrawn from the vial and a gas, such as air, can enter thevial to passively compensate for any changes in fluid volume. This isnecessary because the vial is a closed system and the air vent permitsambient pressure to be maintained inside this reservoir. The gas inletmay also comprise a filter to avoid contamination of the reservoir andany fluid therein and a slight positive pressure may also be maintainedin the gas inlet to keep fluid out of the gas inlet.

Alternatively, fluid in a vial, or other reservoir, comprising a septumcan be placed in fluid communication with the apparatus when the vialcomprising a septum is in the vertical orientation by pushing the vialup onto one or more needles, or other structures, downwardly through theseptum such that the needle forming the outlet channel passes through aheadspace containing a gas in the vial and into the fluid below and theneedle forming the gas inlet channel remains in the headspace, withoutentering the fluid below, to prevent fluid from entering the gas inlet.Thus, those of ordinary skill in the art will recognize that in theapparatus of the disclosure a reservoir may be placed in a variety oforientations.

In some embodiments, the gas inlet and the outlet channel can beadjustable to accommodate different fluid volumes or headspace volumesin different size vials or changes in those volumes as the apparatus isoperated. For example, the gas inlet, or the outlet channel, can beaxially moveable, relative to an axis passing through the reservoir, toaccommodate different fluid volumes or headspace volumes in differentsize vials or changes in those volumes as the apparatus is operated

After delivery of the desired amount of fluid to the apparatus, the vialmay be removed from the apparatus and discarded. A typical protocol fordelivery of a therapeutic agent might include a post-delivery flush ofthe apparatus of the disclosure with distilled water, saline, oralcohol. Vials, or other reservoir structures, containing sterilesamples of these fluids can be prepared ahead of time to facilitate thedelivery of these fluids to the apparatus. After delivery and cleaning,a safety cap may be placed over one or more of the needles, or otherstructures, forming the outlet channel or gas inlet to controlcontamination of the apparatus when it is not in use. The safety cap maybe fastened in place over such needles, or other outlet channels and/orgas inlets, using any appropriate fastener structure such as clips,threads, snaps and the like. Thus, in some embodiments the apparatus ofthe disclosure may lack a reservoir. Additionally, in some embodimentsthe apparatus of the disclosure can comprise a platform which supportsat least one of the outlet channel and the gas inlet, a fastener on theplatform such as threads and, optionally, a safety cap that can beattached to the fastener when a reservoir is absent. Alternatively, theplatform can support the reservoir, such as a vial with a septum, placedin a vertical orientation so that a headspace containing a gas isadjacent to the septum and located above a fluid in the reservoir.

FIG. 11 and FIG. 12 show, from side perspectives, one embodiment of areservoir of an apparatus of the disclosure. In this embodiment, thereservoir 1101, 1201 may comprise a graduated vial sealed with a septum1141, 1241. The septum 1141, 1241 can be pierced with a needlecomprising an outlet channel 1102, 1202 through which a fluid 1242 inthe reservoir 1101, 1201 may be transferred to a low pressure pump inletand comprising a gas inlet 1138, 1238 to admit a gas, such as air, intothe reservoir to compensate for the volume fluid transferred out of thereservoir 1101, 1201. In this embodiment the apparatus may comprise aplatform 1140, 1240, such as an apparatus housing, which can support thereservoir 1101, 1201 and may comprise threads 1139, 1239 or anothersuitable structure for securing a safety cap over the outlet channel1102, 1202 and gas inlet 1138, 1238. Although FIG. 11 and FIG. 12 showthe tubes forming the outlet channel 1102, 1202 and gas inlet channel1138, 1238 placed coaxially, the two tubes could also be separated,provided that the distance between them is sufficient to for the septum1141, 1241 to form a complete seal around each tube.

In the apparatus of the disclosure the outlet channel may be any openingin the reservoir though which a fluid can exit the reservoir. It ispreferred that the outlet be located at the bottom of a verticallypositioned reservoir so that fluid transferred from the reservoir willnot contain bubbles that could interfere with the formation of aerosols.The outlet may also be placed at other appropriate locations on thereservoir and fluid transferred from the reservoir can enter a degasserwhere any bubbles or dissolved gases are removed. The DEGASSEX™ SolventDegasser having part number EHO-5847 and described as a 4-ChannelDEGASSEX™ DG-4400 from PHENOMENEX™ (Torrance, Calif.) is one example ofsuch a degasser. Those of ordinary skill in the art will recognize otherappropriate types of degassers such as vacuum degassers, filter baseddegassers and others.

In the apparatus of the disclosure the high pressure pump can be of anyknown type capable of maintaining flow rates through an aerosolizer andgenerating high back pressures or producing a high pressure fluid at aflow rate sufficient to form an aerosol. One example of a high pressurepump is a high pressure liquid chromatography (HPLC) pump capable ofproducing fluid flow rates of about 16 mL per minute at a fluid pressureof at least about 3,000 pounds per square inch. The Waters Model 590HPLC pump (Waters Corp., Milford, MA) is an example of such a such highpressure pump. Those of ordinary skill in the art will recognize otherhigh pressure pumps. The desired flow rates and fluid pressures can alsobe achieved by operating two or more pumps, such as Waters Model 515pumps, in parallel, or by using upgrade kits to improve flow rates.

Many other different types of high pressure pumps are also known in theart. Those of ordinary skill in the art will recognize, for example,that these different types of high pressure pumps may includereciprocating pumps, rotary pumps, lobe pumps, centrifugal pumps,diaphragm pumps and peristaltic pumps with the caveat that the pumpmaterials must not contaminate, or be contaminated, by the fluid beingpumped.

In a typical reciprocating pump the back-and-forth motion of pistonsinside of cylinders, typically coupled with appropriate check valves,provides the flow of fluid. Reciprocating pumps operate on the positiveprinciple, that is, each stroke delivers a definite volume of liquid tothe system. Several types of pumps, such as the radial piston and axialpiston, are also classified as reciprocating pumps. These pumps aresometimes classified as rotary pumps, because a rotary motion isimparted to the pumps by the source of power. However, the actualpumping is typically performed by sets of pistons reciprocating insidesets of cylinders. High pressure pumps for HPLC are typically highvolume, reciprocating pumps. Appropriate reciprocating pumps areavailable from Waters Corp., Scientific Systems, Inc. (State College,Pa.) and Idex, Inc./Sapphire Engineering, Inc. Idex pumps are positivedisplacement pumps. In a positive displacement pump, the piston positionin the cylinder may be controlled by an optical encoder. Thus, an entireaerosol dose, such as 250 μL, can be delivered in one “shot” and thecylinder is then reloaded for the next delivery. There is no pulsation.It is preferred such pumps are capable of producing fluid flow rates ofabout 16 mL/min at a fluid pressure of at least 3,000 pounds per squareinch.

All rotary pumps have rotating parts which trap the fluid at the inletand force it through an outlet. Gears, screws, lobes, and vanes arecommonly used to move the fluid. Rotary pumps are positive displacementpumps of the fixed displacement type. Rotary pumps are designed withvery small clearances between rotating parts and stationary parts tominimize slippage from the outlet side back to the inlet side.

A lobe pump employs a lobed element or rotor for pushing liquid. Thereare generally only two or three lobes on each rotor. The two lobedelements are rotated, one directly driven by the source of power, andthe other through timing gears. As the elements rotate, liquid istrapped between two lobes of each rotor and the walls of the pumpchamber and carried around from the suction side to the discharge sideof the pump. As liquid leaves the suction chamber, the pressure in thesuction chamber is lowered and additional liquid is forced into thechamber from the reservoir. The lobes are constructed so there is acontinuous seal at the points where they meet at the center of the pump.The lobes of the pump are sometimes fitted with small vanes at the outeredge to improve the seal of the pump. The vanes are mechanically held intheir slots, but with some freedom of movement. Centrifugal force keepsthe vanes snug against the chamber and the other rotating members. Lobepumps with rubber lobes, for example, have been used to process fluidscontaining suspended solids such as, particulates or soft masses.

Centrifugal pumps are classified into three categories: radial, axial,or mixed flow. Radial flow centrifugal pumps develop pressure wholly bycentrifugal force. Axial flow centrifugal pumps develop pressure by thepropelling or lifting action of the vanes of the impeller on the liquid.Mixed flow centrifugal pumps develop pressure partly by centrifugalforce and partly by the lift of the vanes of the impeller on the liquid.The two main components of a centrifugal pump are the impeller and thevolute. The impeller produces liquid velocity and the liquid todischarge through the volute chamber and out of the pump. A centrifugalpump impeller slings the liquid out of the volute. It does not cup theliquid.

Diaphragm pumps are positive displacement pumps using a single or doublediaphragm arrangement to move fluids through a chamber. In doublediaphragm pumps, as the diaphragms move forward, fluid fills the aftchamber while fluid exits from the forward chamber. When the diaphragmsmove to the aft position, fluid enters the forward chamber and exits theaft chamber. This process repeats itself resulting in a smooth positiveflow.

Peristaltic pumps work on the principle of sequential narrowing of thediameter of a shaft or portion of tubing in order to move liquid alongthe length of the tubing. The fluid is totally contained within a tubeor hose and does not come into contact with the pump. They have noseals, glands or valves. This means they are ideal for hygienic orsterile operation. Being true positive displacement, there is no slip orback flow.

In the apparatus of the disclosure the switching valve can be a threeway valve, a four way valve or any similar valve structure, orarrangement of valves, that can be configured to transfer a fluid thoughat least one delivery outlet or at least one release outlet. A rotaryvalve is one example of a switching valve, shear-type valve, having twoflat surfaces with a gasket in between and appropriate holes in thesurfaces and parts so that valving is achieved when the two surfaces aremoved relative to one another. A switching valve may be placed in agiven configuration by hydraulic actuation, pneumatic actuation, manualactuation, solenoid actuation, motor actuation or combinations of these.A switching valve can also be activated manually, without an interveningcontroller, using a small handle or similar structure to switch betweenvalve configurations. One example of a switching valve is an injectionvalve for HPLC such as the Idex Health and Science (Oak Harbor, Wash.)RHEODYNE™ model 7725 injection valve, the RHEODYNE™ model 7725iinjection valve and the RHEODYNE™ model 9725 injection valve. TheRHEODYNE™ model 7010 valve is another example of a switching valve.Those of ordinary skill in the art will recognize other examples ofswitching valves.

The switching valve also affects the quality of the spray emanating fromthe tip of an aerosolizer. This is because the quality of the spray(mass median diameter, cone angle) emanating from the tip of anaerosolizer is a direct function of the pressure of a liquid beingsprayed. It is also preferred that the mean median mass diameter of thedispersed phase in the aerosol be in a range of about 8 μm to about 22μum. This means that the build-up and decay of the pressure exerted by afluid at the delivery outlet in fluid communication with a switchingvalve must occur very rapidly so the aerosol quality does not decay andresult in a liquid stream or the formation of very large liquid drops.Thus, it is preferred that the switching valve be able to handle a cycleof pressure build up and decay, such as at the delivery outlet, that isvery rapid and occurs, for example, at about 200 milliseconds to about500 milliseconds. In particular, it is preferred that switching totransfer a fluid though either the delivery outlet or the release outletis performed by the switching valve in about 200 to 500 milliseconds orless.

A switching valve may be coupled to an actuator and can be controlledelectrically so that the open and closed positions of the valve can beregulated by a controller. In the “on” configuration of a switchingvalve, a high pressure fluid is released into the delivery outlet anddirected into the aerosolizer. In the “off” configuration of a switchingvalve, a high pressure fluid is transferred from the release outlet intoa restrictor and a fluid, with low pressure, is released.

In the apparatus of the disclosure, the aerosolizer may be sized forinsertion into an opening in a patient body or for placement adjacent toa target tissue such as the lungs. Such an aerosolizer may comprise agenerally elongated sleeve member which defines a first end and a secondend and includes a longitudinally extending opening therethrough. Thefirst end of the sleeve member is placed in fluid communication with thedelivery outlet of the switching valve or the high pressure pump outlet.A generally elongated insert is also provided. The generally elongatedinsert defines a first end and a second end and is received within atleast a portion of the longitudinally extending opening of the sleevemember. The insert includes an outer surface which has at least onesubstantially helical channel provided that surrounds its outer surfaceand extends from the first end to the second end. The substantiallyhelical channel of the insert is adapted to pass the liquid materialwhich is received by the sleeve member. A generally elongated bodymember is also included which is in connection with the sleeve member.The body member includes a cavity provided in its first end whichterminates at an end wall which is adjacent its second end. The end wallis provided having an orifice therein for spraying the fluid which isreceived from the insert. This spraying permits liquids, solids, ormixtures of these to be released and entrained in a gas, such as air, toproduce an aerosol. Examples of aerosolizers of this type arecommercially available from Penn-Century, Inc. (Philadelphia, Pa.) andare also described in, for example, U.S. Pat. Nos. 5,579,758, 5,606,789,5,594,987, 6,016,800, 6,029,657 and 6,041,775.

An aerosolizer may also comprise any orifice through which a liquid,such as droplets, are released and entrained in a gas to produce aliquid aerosol. An aerosolizer may also comprise an orifice throughwhich a gas passes into a fluid to produce a liquid aerosol. Anaerosolizer may comprise an orifice through which solids, such asparticulates, are released and entrained in a gas to produce a solidaerosol. An aerosolizer may also comprise an orifice through which a gaspasses into a solid, such as a collection of particulates or a friablesubstance, to produce a solid aerosol. Aerosolizers for forming solidaerosols may have a compartment containing solids, such as friablesolids or particulates, connected to a conduit containing a fluid sothat the solid can be incorporated into the fluid. Aerosolizers may alsocomprise elements, such as ultrasonic probe elements, that can generateliquid droplets or particulates, that are released and entrained in agas to produce an aerosol. Alternatively, an aerosolizer may compriseheating and cooling elements that vaporize a liquid and then partiallycondense the liquid, or condense the liquid to form droplets that arereleased and entrained in a gas to produce a liquid aerosol. Anaerosolizer may also comprise heating and cooling elements that vaporizea solid and then partially, or completely, condense the solid to formparticulates that are released and entrained in a gas to produce a solidaerosol. An aerosolizer may also comprise combinations of structuresthat produce an aerosol. Those of ordinary skill in the art will alsorecognize other aerosolizer structures.

An aersolizer may comprise an extension connected to the portion of theaerosolizer containing the orifice, or other opening through which anaerosol is released. Such an extension can facilitate the delivery of anaerosol to a target tissue. The extension may be constructed ofdifferent materials, such as rigid or flexible materials. For example,the extension may be constructed from any flexible material such as alaminate, fiber reinforced polymer, metal and metal alloy orcombinations of these. The extension can be constructed from polymers orcombinations of polymers such as, for example, a polyether ether ketone(PEEK), polytetrafluoroethylene (PTFE), fluorinated ethylene propylene,ethylene tetrafluoroethylene (ETFE) and the like. The extension may be apipe, such as tubing, or other fittings, such as a ball joint, whichcontains an interior passage suitable for fluid communication. Theextension may also be articulated to accommodate insertion into bodycavities or openings such as, for example, the trachea or a surgicalincision. In particular, the aerosolizer and/or extension may beinserted into a body cavity through an opening created by tracheostomyor tracheotomy such as, for example, a tracheal port. The aerosolizerand/or extension may also simply be inserted down the throat and intothe trachea. The extension may also have any shape that facilitates thedelivery of an aerosol to a target tissue. For example, the extensionmay have a rounded shape, a cup-like shape, a curved shaped or a bulbousshape to facilitate the placement of an aerosolizer adjacent to a targettissue and the delivery of aerosol. The extension may also be of anumber of different lengths to facilitate delivery of aerosol. Forexample, an extension to facilitate delivery of aerosol to the nasalpassages may have a shorter length than an extension to facilitate thedelivery of an aerosol adjacent to the carina. The extension may alsocomprise at least one sensor such as, for example, temperature, pressureor humidity sensors. The aerosolizer and/or extension may also beinserted into body cavities or other opening through a port in and maybe associated with a bronchoscope or other instrumentation.

FIG. 1 shows one embodiment of an apparatus of the disclosure. In thisembodiment a reservoir 101 contains a fluid that exits the reservoirthrough the outlet channel 102 and then enters a low pressure pump inlet103. The fluid then passes from the low pressure pump inlet 103 into ahigh pressure pump 104 and enters a high pressure pump outlet 105. Thefluid then passes from the high pressure pump outlet 105 into aswitching valve 106 having a delivery outlet 107 and a release outlet108. The fluid flow from the switching valve 106 is regulated by acontroller 113 which controls the configuration of the switching valve106. When the switching valve 106 is configured to produce an aerosol,the fluid passes through a delivery outlet 107 and into an aerosolizer109 to produce an aerosol. A flexible connector 112, such as a coil, maybe placed between the delivery outlet 107 and aerosolizer 109 such thatfluid passing from the delivery outlet 107 enters the flexible connector112 and then passes into the aerosolizer 109. When the switching valve106 is configured not to produce an aerosol, the fluid passes through arelease outlet 108 and enters a restrictor 110. The fluid is thenreleased and can enter an appropriate vessel or conduit. The apparatusof the disclosure is capable of delivering samples of any volume fromabout 250 μL, with the preferred total sample volumes being about 10 mLto about 20 mL. Delivery is preferably made in the form of discrete,timed aliquots chosen by the operator. It is preferred that theapparatus of the disclosure delivery aerosol volumes of about 10 mL toabout 20 mL. The apparatus of the disclosure is also capable ofdelivering samples of any other volume including volumes of about 10 μLor greater. For example, volumes of about 10 μL or about 125 μL aredesirable for delivery to both pulmonary tissues and non-pulmonarytissues in some patients.

FIG. 2 shows one example of a switching valve. The switching valve 206has a high pressure pump inlet 205, a delivery outlet 207 and a releaseoutlet 208. The fluid flow from the switching valve 206 is regulated bya controller 213 which controls the configuration of the switching valve206. When the switching valve 206 is configured to produce an aerosol,the fluid passes through a delivery outlet 207. When the switching valve206 is configured not to produce an aerosol, the fluid passes through arelease outlet 208 and enters a restrictor 210. The fluid is thenreleased from the switching valve 206 and can then enter an appropriatevessel or conduit.

FIGS. 3 and 4 show one example of an aerosolizer. The MICROSPRAYER®Aerosolizer Model IA-1B available from Penn-Century, Inc. (Philadelphia,Pa.) is an example of such an aerosolizer. The aerosolizer 319, 419 inthis example comprises a body member 320, 420, as best seen in FIG. 3,that is comprised of a hollow tube member. A first end of the bodymember 320, 420 is provided with a cavity extending therein whichterminates by an end wall 330, 430 provided adjacent its second end. Inthis example, the end wall 330, 430 is provided with an orifice 331, 431extending through the length thereof As best seen in FIG. 4, theconfiguration of the orifice 331, 431 in this example of an aerosolizerpreferably includes a central area of substantially constant diameterand areas which are tapered or substantially conical-shaped at each endthereof In alternative embodiments, the aerosolizer may have only oneconical-shaped end and another end that is flat. Such alternativeaerosolizer embodiments are described in, for example, U.S. Pat. No.6,016,800. The MICROSPRAYER® Aerosolizer Model IA-1C available fromPenn-Century, Inc. (Philadelphia, Pa.) is an example of such analternative aerosolizer embodiment. In this example of an aerosolizer,the body member 320, 420 is preferably comprised of 17-gauge extra-thinwall stainless steel tubing, which includes an outer diameter of 0.058inches and an inner diameter of 0.050 inches. However, other suitablematerials in any suitable configuration can be utilized for this samepurpose.

In the example of an aerosolizer shown in FIG. 4, the insert 318, 418 isplaced within the sleeve member 317, 417 and the sleeve member 317, 417and body member 320, 420 are connected to each other to form theaerosolizer 319, 419. An aerosolizer can have the dimensions of asub-miniature aerosolizer and be sufficiently small for intratrachealinsertion, such as into an endotracheal tube, insertion into abronchoscope, or insertion into the trachea directly. The aerosolizer ofthis example can be formed by providing a threaded channel 433 in thesleeve member 317, 417 that is tap formed in the inner surface. In analternative embodiment of the aerosolizer, the tube end may be swagedwith a hardened pin and the threaded insert secured with a smallindentation. The end of the sleeve member 317, 417 is also preferablydrilled to an inner diameter of 0.036 inches for a distance of 0.100inches prior to providing the threaded channel 433, after which, thebored end is preferably tapped with a 1 mm×0.025 mm taper tap sufficientto provide a space of 0.020″ length between the second end of insert318, 418 and the second end of sleeve member 317. In the aerosolizer ofthis example, the threaded channel 433 is substantially helical andformed from threads 332, 432 on insert 318, 418.

Importantly, when used in conjunction with the Penn-CenturyMICROSPRAYER® Aerosolizer Model IA-1C, or other aerosolizers, thedisclosed apparatus is suitable for the on-demand delivery of liquidaliquots of any volume, as small as 250 μL, in the form of a relativelyfine spray from the end of a long, thin tube (e.g., 0.025″ diameter). Itis also preferred that the aerosolizer be suitable for the delivery oftotal volumes of aerosol from about 10 mL to about 20 mL. Theaerosolizer may also be suitable for delivering samples of any othervolume including volumes of about 10 μL or greater. For example, volumesof about 10 μL or about 125 μL are desirable for delivery to bothpulmonary tissues and non-pulmonary tissues in some patients. The tipresistance of the IA-1C aerosolizer is such that a flow of 16.2 mL/min(270 μL/sec) generates a back pressure of about 3,000 psi and results ina spray with a particle size distribution of 8-22 μm (mass mediandiameter). The volume of liquid delivered per aliquot depends upon thelength of time the system is maintained in an aerosol deliveryconfiguration and the total delivered volume ultimately depends onlyupon the size of the reservoir from which the sample is drawn.

In the apparatus of the disclosure, the restrictor may be a pipe,fitting or combinations of these which provide sufficient flowresistance so that pressure is maintained on the inlet side of therestrictor. One example of a restrictor is a pipe comprising an inletside and an outlet side in which the cross-sectional area of theinterior passage within the pipe is tapered so that the cross-sectionalarea of the interior passage on the inlet side is greater than thecross-sectional area of the interior passage on the outlet side of thepipe. Another example of a restrictor comprises an inlet having a firstcross-sectional area, an outlet and a porous solid between the inlet andoutlet that produces a second cross-sectional area in the porous solidthat is smaller than the first cross-sectional area. In the apparatus ofthe disclosure, a restrictor may be in fluid communication with avessel, such as the reservoir, or a waste vessel. Alternatively, arestrictor may deliver a fluid to a drain or a fluid distribution systemsuch as a sewer system. A restrictor may also be in fluid communicationwith a release outlet return.

An example of a restrictor is shown in FIG. 2. A restrictor 210 isprovided as a fitting with an inlet side 215 and outlet side 216 thatcomprises a portion of interior passage 211 that is 2.5 inches in lengthwith a substantially circular cross-section and a diameter of 0.005inches. The flow resistance of the restrictor can be “tuned” byadjusting the length. Stated differently, the resistance of therestrictor can be matched to the resistance of the aerosolizer byadjusting the length of the restrictor.

High pressure back pressure regulator No. P-880 from Upchurch Scientific(Oak Harbor, Wash.) is another example of a restrictor and is adjustablebetween 2,000 and 5,000 psi.

One embodiment of the disclosure is an apparatus, wherein the switchingvalve contains a fluid at high pressure and the restrictor maintains thefluid at high pressure in the switching valve when the switching valvedelivers the fluid to the release outlet.

Another embodiment of the disclosure is an apparatus, wherein therestrictor comprises an interior passage of 2.5 inches in length with asubstantially circular cross-section and a diameter of 0.005 inches.

Another embodiment of the disclosure is an apparatus, further comprisinga flexible connector in fluid communication with the delivery outlet andthe aerosolizer, said flexible connector connecting both the deliveryoutlet and the aerosolizer.

The flexible connector may be a pipe, such as tubing, or other fittings,such as a ball joint, which contains an interior passage suitable forfluid communication. The flexible connector can be constructed from anyflexible material such as a laminate, fiber reinforced polymer, metaland metal alloy or combinations of these. The flexible connector can beconstructed from polymers or combinations of polymers such as, forexample, a polyether ether ketone (PEEK), polytetrafluoroethylene(PTFE), fluorinated ethylene propylene, ethylene tetrafluoroethylene(ETFE) and the like. The flexible connector can have any geometry suchas a coil, zig-zag and the like suitable for the extension, placementand refraction of a connected aerosolizer. Coil configurations maycontain circular coils of varying diameters, number of coils and lengthsof substantially linear tails. A helical coil is one example of such acoil configuration. Ideally, the flexible connector is suitable fornon-contaminating fluid communication.

It is preferred that the flexible connector be constructed from tubingmade of a polymer, such as PEEK, have a 1/16 inch outside diameter andan interior passage with a substantially circular cross section and a0.02 inch inside diameter.

Another embodiment of the disclosure is an apparatus, wherein theflexible connector comprises a coil.

Another embodiment of the disclosure is an apparatus, wherein theflexible connector comprises a polyether ether ketone.

Another embodiment of the disclosure is an apparatus, wherein theswitching valve is connected to a controller.

Another embodiment of the disclosure is an apparatus, wherein thecontroller is programmed to open the switching valve for a pre-set timeinterval.

Examples of controllers include personal computers, programmable logiccontrollers, circuits, switches, computer chips and combinations ofthese. A controller can also regulate the pressure, fluid flow andtemperature of fluids in a switching valve to modulate the formation ofliquid aerosols. A controller may affect the operation of a switchingvalve and the formation of liquid aerosols by feedback type control,feedforward type control or a combination of these control types. Acontroller may also utilize fuzzy logic to affect the operation of aswitching valve.

The controller can comprise an electrical, or mechanical switch, such asa foot activated switch or a simple finger activated switch. The switchmay be a push button switch conveniently located next to theaerosolizer. Other switch configurations may be used as well includinglever type switches. The switch can provide momentary activation,sustained activation (e.g., push-on) and cut off activation (e.g.,push-off) of the aerosol. The controller may also comprise at least onesensor that can monitor parameters such as pressure, fluid flow,humidity, temperature, the optical density or absorption of a medium,such as a liquid aerosol, and the like. For example, the controller canalso comprise a pressure sensor and can be activated by feedback fromthe pressure sensor. The pressure sensor can be placed in the trachea ofa patient so that a liquid aerosol is delivered upon inhalation when thepressure in the trachea decreases. The controller may also comprise atimer so that the production, and administration, of a liquid aerosolmay be coordinated with the inhalation phase of a patient's breathingcycle. The controller may also comprise a force transducer, which whenlocated on or around a patient's thorax, produces a signal correspondingto the inhalation phase of a patient's breathing cycle. Such respirationsensors are commercially available and include the PASSPORT™ respirationsensor belt PS-2133 Respiration Rate (PASCO Scientific, Inc., Roseville,Calif.) as well as the respiration monitor belt available from VernierSoftware & Technology (Beaverton, Oreg.) and others.

The controller may comprise a hand piece that can be configured so theaerosolizer is positioned to form an angle of about 90° (FIGS. 6 and 9),about 135° (FIGS. 7 and 10), about 180° (FIG. 8), or any otherconvenient angle, between a long axis of the hand piece and a long axisof an aerosolizer. The hand piece can also comprise a button switch, orother switch, connected to a controller by electrical leads. Theelectrical leads and switch can form a circuit in the controller and maycontrol aerosol production by the apparatus. The button switch can bepositioned to accommodate activation by a thumb or other finger as shownin FIGS. 6 to 9. The hand piece may also comprise a housing of rigid orflexible materials and the housing may be of any appropriateconfiguration, or shape, suitable for being held by hand.

FIGS. 6 to 9 show, from a side perspective, one embodiment of acontroller of an apparatus of the disclosure. FIG. 10 shows, from a sideperspective, a cross-section through a long axis of one embodiment of acontroller of an apparatus of the disclosure. In these embodiments thecontroller of the apparatus comprises a housing 635, 735, 835, 935, 1035defining an interior lumen as well as having a first end and a secondend which define a long axis. A button switch 634, 734, 834, 934, 1034is located proximal to the first end of the housing 635, 735, 835, 935,1035 and an aerosolizer 609, 709, 809, 909, 1009 is also locatedproximal to the first end of the housing 635, 735, 835, 935, 1035 toform an appropriate angle with a long axis of the housing and a longaxis of the aerosolizer. Thus, in these embodiments the button switch634, 734, 834, 934, 1034 and the aerosolizer 609, 709, 809, 909, 1009are proximally connected to the first end of the housing 635, 735, 835,935, 1035. The aerosolizer 609, 709, 809, 909, 1009 is in fluidcommunication with a flexible connector 612, 712, 912. The aerosolizer609, 709, 809, 909, 1009 and flexible connector 612, 712, 912 may bejoined by a length of tubing located partially, or completely, withinthe housing and this tubing may exit the housing proximal to the secondend of the housing 635, 735, 835, 935, 1035. The button switch 634, 734,834, 934, 1034 is connected to a first electrical lead 636, 736, 936,1036 and a second electrical lead 637, 737, 937, 1037 and the leads 636,736, 936, 1036, 637, 737, 937, 1037 are connected to a controller suchthat the controller comprises the button switch 634, 734, 834, 934,1034. The first electrical lead 636, 736, 936, 1036 and secondelectrical lead 637, 737, 937, 1037 may be located partially, orcompletely, within the housing 635, 735, 835, 935, 1035 and may exit thehousing proximal to the second end of the housing 635, 735, 835, 935,1035. If the tubing is straight, the electrical leads and the tubing canbe bundled in a flexible package.

In the apparatus and methods of the disclosure the aerosols may beadministered with, or without, being respired by a patient and aerosoladministration is not dependent on the respiratory capacity, function orhealth of a patient. This means the apparatus and methods of thedisclosure make it possible to safely deliver far greater volumes thanwould be feasible in patients with compromised lung function, can beused in populations that cannot use inhalers (i.e., infants, theelderly, patients in a coma or unconscious, etc.) and that the dispersedphase in an aerosol need not be in a respirable range (e.g., 1-5 μm) toget past the body's anatomical barriers because the disclosed apparatusis carrying the aerosol past such barriers.

The controller may also be programmed to open a switching valve, oractivate a high pressure pump, for a pre-set period of time to regulatethe formation of liquid aerosols. These pre-set periods of time mayinclude any time interval, such as 200 ms. These periods of time mayalso be constant time intervals or combinations of time intervals. Forexample, in a controller comprising a button switch, the activation ofthe switch would send a signal to a controller programmed to open theswitching valve, or activate a high pressure pump, for a pre-set periodof time and the controller would then open the switching value, or highpressure pump, for the pre-set period of time. After the pre-set periodof time has elapsed, the controller would close the switching valve ordeactivate the high pressure pump. A timer is one example of such acontroller. An example of such a programmable controller is the OmegaModel No. PTC-15 timer (OMEGA Engineering, Inc., Stamford, Conn.).

Another embodiment of the disclosure is an apparatus, wherein theaerosolizer comprises a substantially helical channel.

Another embodiment of the disclosure is an apparatus, wherein thecontroller comprises a housing with a first end and both the aerosolizerand a switch are proximally connected to the first end of the housing.

Another embodiment of the disclosure is an apparatus, further comprisinga flexible connector in fluid communication with the delivery outlet andthe aerosolizer, said flexible connector connecting both the deliveryoutlet and the aerosolizer, and wherein the switch further comprises anelectrical lead.

Another embodiment of the disclosure is an apparatus, wherein thereservoir comprises a gas inlet.

Another embodiment of the disclosure is an apparatus, wherein thereservoir further comprises a septum containing the outlet channel andthe gas inlet.

Another aspect of the disclosure is an apparatus comprising a reservoirin fluid communication with an outlet channel; a low pressure pump inletin fluid communication with the outlet channel; a high pressure pump influid communication with the low pressure pump inlet; a high pressurepump outlet in fluid communication with the high pressure pump; aswitching valve in fluid communication with the high pressure pumpoutlet, said switching valve containing a fluid at high pressure andhaving a delivery outlet and a release outlet; a controller connected tothe switching valve; a flexible connector in fluid communication withthe delivery outlet; an aerosolizer in fluid communication with theflexible connector; and a restrictor in fluid communication with therelease outlet.

Another embodiment of the disclosure is an apparatus, wherein therestrictor maintains the fluid at high pressure in the switching valvewhen the switching valve delivers the fluid to the release outlet.

Another aspect of the disclosure is an apparatus comprising a reservoirin fluid communication with an outlet channel; a low pressure pump inletin fluid communication with the outlet channel; a high pressure pump influid communication with the low pressure pump inlet; a high pressurepump outlet in fluid communication with the high pressure pump; and anaerosolizer in fluid communication with the high pressure pump outlet.

Another embodiment of the disclosure is an apparatus, further comprisinga flexible connector in fluid communication with the high pressure pumpoutlet and the aerosolizer, said flexible connector connecting both thehigh pressure pump outlet and the aerosolizer.

Another embodiment of the disclosure is an apparatus, wherein the highpressure pump is connected to a controller.

Another embodiment of the disclosure is an apparatus, wherein thecontroller is programmed to activate the high pressure pump for apre-set time interval.

Another aspect of the disclosure is an apparatus, further comprising aflexible connector in fluid communication with the high pressure pumpoutlet and the aerosolizer, said flexible connector connecting both thehigh pressure pump outlet and the aerosolizer, and wherein the switchfurther comprises an electrical lead.

Another aspect of the disclosure is an apparatus comprising a reservoirin fluid communication with an outlet channel; a low pressure pump inletin fluid communication with the outlet channel; a high pressure pump influid communication with the low pressure pump inlet; a high pressurepump outlet in fluid communication with the high pressure pump; acontroller connected to the high pressure pump; a flexible connector influid communication with the high pressure pump outlet; and anaerosolizer in fluid communication with the flexible connector.

FIG. 13 shows one embodiment of an apparatus of the disclosure. In thisembodiment a reservoir 1301 contains a fluid that exits the reservoirthrough the outlet channel 1302 and then enters a low pressure pumpinlet 1303. The fluid then passes from the low pressure pump inlet 1303into a high pressure pump 1304 and enters a high pressure pump outlet1305. The fluid then passes from the high pressure pump outlet 1304 intoan aerosolizer 1309 to produce an aerosol when the high pressure pump1304 is operated. A flexible connector 1312, such as a coil, may beplaced between the high pressure pump outlet 1305 and aerosolizer 1309such that fluid passing from the high pressure pump outlet 1305 entersthe flexible connector 1312 and then passes into the aerosolizer 1309.The apparatus of the disclosure is capable of delivering samples of anyvolume from about 250 μL, with the preferred total sample volumes beingabout 10 mL to about 20 mL. Delivery is preferably made in the form ofdiscrete, timed aliquots chosen by the operator or is regulated by acontroller 1313 programmed to activate the high pressure pump for apre-set time interval. The controller may be activated by an operatorcontrolled switch or automation activated such as by a sensor. Theapparatus of the disclosure is also capable of delivering samples of anyother volume including volumes of about 10 μL, or greater. For example,volumes of about 10 μL, or about 125 μL, are desirable for delivery toboth pulmonary tissues and non-pulmonary tissues in some patients.

Another aspect of the disclosure is an apparatus comprising a reservoirin fluid communication with an outlet channel and a release outletreturn; a low pressure pump inlet in fluid communication with the outletchannel; a high pressure pump in fluid communication with the lowpressure pump inlet; a high pressure pump outlet in fluid communicationwith the high pressure pump; a switching valve in fluid communicationwith the high pressure pump outlet, said switching valve containing afluid at high pressure and having a delivery outlet and a releaseoutlet; a controller connected to the switching valve; a flexibleconnector in fluid communication with the delivery outlet; anaerosolizer in fluid communication with the flexible connector; and arestrictor in fluid communication with the release outlet and therelease outlet return and that maintains the fluid at high pressure inthe switching valve.

FIG. 5 shows another embodiment of an apparatus of the disclosure. Inthis embodiment a reservoir 501 contains a fluid that exits thereservoir through the outlet channel 502 and then enters a pressuregenerator 515. In particular, the fluid enters a low pressure pump inlet503. The fluid then passes from the low pressure pump inlet 503 into ahigh pressure pump 504 and enters a high pressure pump outlet 505. Thefluid then passes from the high pressure pump outlet 505 into aswitching valve 506 having a delivery outlet 507 and a release outlet508. The fluid flow from the switching valve 506 is regulated by acontroller 513 which controls the configuration of the switching valve506. When the switching valve 506 is configured to produce an aerosolthe fluid passes through a delivery outlet 507 and into a aerosolizer509 to produce an aerosol. In this embodiment, an extension 516 isconnected to the aerosolizer 509. A flexible connector 512, such as acoil, may be placed between the delivery outlet 507 and aerosolizer 509such that fluid passing from the delivery outlet 507 enters the flexibleconnector 512 and then passes into the aerosolizer 509. When theswitching valve 506 is configured not to produce an aerosol, the fluidpasses through a release outlet 508 and enters a restrictor 510. Thefluid then enters a release outlet return 514 on the reservoir 501 sothat the fluid released can enter the reservoir 501.

The release outlet return may be a fitting, pipe or armature whichcomprises an interior passage, or opening, located on the reservoirthrough which a fluid can be transferred, directly or indirectly, intothe reservoir.

Another embodiment of the disclosure is an apparatus, wherein therestrictor comprises an interior passage of 2.5 inches in length with asubstantially circular cross-section and a diameter of 0.005 inches, andthe flexible connector is a coil comprising a polyether ether ketone.

Another embodiment of the disclosure is an apparatus, wherein the switchfurther comprises an electrical lead.

Another aspect of the disclosure is a method of administering an aerosolto a patient comprising providing an apparatus of the disclosure;placing the aerosolizer adjacent to a target tissue in a patient; andoperating the apparatus to produce an aerosol; whereby an aerosol isadministered to the patient.

In the methods of the disclosure, the aerosolizer can be placed adjacentto any target tissue in a patient. This may be accomplished by placingthe aerosolizer adjacent to any external part of a patient's body suchas the skin, eyes, and the like. This may also be accomplished byinserting the aerosolizer into an opening in a patient's body. Suchopenings may be naturally occurring or created by minimally invasive orinvasive procedures. Examples, of such procedures include tracheotomy,tracheostomy, minitracheotomy, minitracheostomy, scopic procedures, andopen surgical procedures. In some instances, it may be necessary toprovide an environment containing a continuous, gaseous medium adjacentto a tissue. This facilitates aerosol formation by providing asufficient amount of a gaseous medium to permit a liquid, such as fluiddroplets, or a solid, such as a particulate, to be entrained in agaseous phase so an aerosol can be formed. Such environments may becreated, or maintained, within a body cavity or organ by gentleinflation of the organ or body cavity with a gaseous medium. Suchenvironments may also be localized to a particular area by the use ofrigid or flexible materials, such as adhesive films or partially openvessels, to define and limit the delivery of an aerosol to a particulararea. An aerosolizer can also be placed adjacent to a target tissue,such as that in the lungs, by insertion into a cavity or passage, suchas the trachea, which is connected to the target tissue.

Such approaches to placing an aerosolizer adjacent to a target tissueare also advantageous because they minimize the amount of aerosoldelivered to non-target tissues. However, in some instances the targettissue may be one that facilitates the delivery of a component of anaerosol to a distal active site. For example, delivery of aerosols tothe lungs may result in the delivery of an aerosol component to theblood stream. Similarly, delivery of aerosols to nervous tissue mayresult in retrograde transport or anterograde transport of an aerosolcomponent to a distal active site.

In the method of the disclosure, the target tissue may be any tissue ina patient's body. For example, such tissues may be epithelial tissues,including mucus membranes associated with body cavities or organs. Suchtissues may also be connective tissues, muscle tissue, and nervoustissue. Tissue within the respiratory tract, such as that in the lungs,is a specific example of a target tissue to which an aerosol can beadministered.

In the methods of the disclosure, an aerosol is administered to apatient. A patient may have any condition requiring the administrationof an aerosol. Such conditions include those produced by cancers,trauma, infection, pain, genetic disorders, hyperthermia, dehydration,hypothermia and xenobiotics. Such conditions may also include tumors(such as non-malignant tumors) and hyperplasia.

The aerosol in the method of the disclosure may comprise a liquid as thedispersed phase. The liquid in the aerosol is in the form of smalldroplets. These droplets may also contain solids, having a mass, orother physical characteristics compatible with the formation of a liquidaerosol. Examples, of such solids include, for example, particlescomprising biodegradable matrices or other solid materials as well ascrystals of pharmaceutically active agents. Such solids can facilitatethe delivery or sustained release of pharmaceutical agents administeredin an aerosol. The liquid in an aerosol may also be water, an aqueoussolution containing ions, an aqueous solution containing vitamins, abuffered aqueous solution, or any other type of aqueous solution orsuspension. Such liquids may be administered to patients with conditionssuch as, for example, dehydration and electrolytic imbalances. Theliquid in an aerosol may also comprise a pharmaceutical agent such as,for example, a small organic molecule, peptide chains, antibodies,antibody fragments, polynucleotides or combinations of these. Otherexamples of agents that can be included in a liquid aerosol include, forexample, antibiotics, anesthetics, bronchodilators, vaccines,anti-inflammatory agents, lipopolysaccharide, neutrophil elastase,inhibitors of neutrophil elastase, surfactants, radioisotopes,epinephrine, heparin, L-dopa, cells, COX-2 inhibitors, gene therapyagents, microparticles and nanoparticles.

The aerosol in the method of the disclosure may also comprise a solid asthe dispersed phase. The solid in the aerosol may be in the form of aparticulate or a friable material. The particulates may also contain aliquid, having a mass, or other physical characteristics compatible withthe formation of an aerosol. Examples, of such solids include, forexample, particles comprising biodegradable matrices or other solidmaterials as well as crystals of pharmaceutically active agents. Suchsolids may also contain a fluid such as a buffer or pharmaceuticallyactive agent. Such solids can facilitate the delivery or sustainedrelease of pharmaceutical agents administered in an aerosol. The solidin an aerosol may also comprise a pharmaceutical agent such as, forexample, a small organic molecule, peptide chains, antibodies, antibodyfragments, polynucleotides or combinations of these. Other examples ofagents that can be included in a solid aerosol include, for example,antibiotics, anesthetics, bronchodilators, vaccines, anti-inflammatoryagents, lipopolysaccharide, neutrophil elastase, inhibitors ofneutrophil elastase, surfactants, radioisotopes, epinephrine, heparin,L-dopa, cells, COX-2 inhibitors, gene therapy agents, microparticles andnanoparticles.

The aerosol in the method of the disclosure also comprises a gas as thecontinuous phase. If other than ambient air, the continuous phase cancomprise one, or more, gases delivered concomitantly with the dispersedphase. For example, the gas in the aerosol can comprise pure oxygen orother oxygen containing mixtures such as, for example, air. Aerosolscomprising oxygen gas can be administered to patients with hypoxicconditions. Mixtures of gases in the aerosol may also be selected toalter the density of the continuous phase and facilitate the suspensionof liquid droplets or increase the residence time of an aerosoldelivered to a target tissue such as, for example, the lungs. Nitrogengas is one example of a gas that may alter the density of the continuousphase or increase residence times of an aerosol in a target tissue. Thegas in the aerosol may also comprise one, or more, pharmaceuticallyactive agents. The gas may comprise alcohols, ethers or other moleculesin the gaseous phase that are pharmaceutically active. For example, thegas may comprise ethanol, diethyl ether or nitrous oxide.

Examples of drugs that may be administered in aerosols to patients aswell as associated diseases or other conditions are listed in Table 1.

TABLE 1

indicates data missing or illegible when filed

Table 2 also lists other conditions, or situations, where aerosoladministration to a patient with the apparatus or methods of thedisclosure may be desirable.

TABLE 2

indicates data missing or illegible when filed

Table 3 also lists examples of compositions and other substances, suchas organisms, which may be administered in an aerosol to a patient withthe apparatus or methods of the disclosure.

TABLE 3

indicates data missing or illegible when filed

The apparatus and methods of the disclosure can also be used to deliveranti-microbial agents such as amoxicillin, ampicillin, tetracyclines,aminoglycosides (e.g., streptomycin), macrolides (e.g., erythromycin andits relatives), chloramphenicol, ivermectin, rifamycins and polypeptideantibiotics (e.g., polymyxin, bacitracin) and zwittermicin. Such agentscan be used, for example, to treat Tuberculosis, Staphlycoccus,Streptococcus, yeast, Serratia, E. coli, and Pseudomonas aeruginosainfections.

The apparatus and methods can also be used to deliver agents such asshort-acting β₂-agonists, long-acting β₂-agonists, anticholinergics,corticosteroids, systemic corticosteroids, mast cell stabilizers,leukotriene modifiers, methylxanthines, β₂-agonists, albuterol,levalbuterol, pirbuterol, artformoterol, formoterol, salmeterol,anticholinergics including ipratropium and tiotropium; corticosteroidsincluding beclomethasone, budesonide, flunisolide, fluticasone,mometasone, triamcinolone, methyprednisolone, prednisolone, prednisone;leukotriene modifiers including montelukast, zafirlukast, and zileuton;mast cell stablizers including cromolyn and nedocromil; methylxanthinesincluding theophylline; combination drugs including ipratropium andalbuterol, fluticasone and salmeterol, budesonide and formoterol;antihistamines including hydroxyzine, diphenhydramine, loratadine,cetirizine, and hydrocortisone; immune system modulating drugs includingtacrolimus and pimecrolimus; cyclosporine; azathioprine;mycophenolatemofetil; inhibitors of matrix metallo proteases (MMPs)including inhibitors of MMP-9 and MMP-2, and combinations thereof.

The apparatus and methods can also be used to deliver agents such asciclosporin, hyaluronic acid, carmellose, macrogol(s), dextran andhyprolose, sodium and calcium, sodium and povidone, hypromellose,carbomer, amikacin, gentamicin, kanamycin, neomycin, netilmicin,streptomycin, tobramycin, paromomycin, geldanamycin, herimycin,loracarbef, ertapenem, imipenem/cilastatin, meropenem, cefadroxil,cefazolin, cefalotin/cefalothin, cephalexin, cefaclor, cefamandole,cefoxitin, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone,cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime,ceftriaxone, cefeprime, teicoplanin, vancomycin, azithromycin,clarithromycin, dirithromycin, erythromycin, roxithromycin,troleandomycin, telithromycin, spectinomycin, aztreonam, amoxicillin,ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin,flucloxacillin, mezlocillin, nafcillin, penicillin, peperacillin,ticarcillin, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin,gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin,ofloxacin, trovafloxacin, mafenide, protosil, sulfacetamide,sulfamethizole, sulfanilamide, sulfasalazine, sulfisoxazole,trimethoprim, trimethoprim-sulfamethoxazole, demeclocycline,doxycycline, minocycline, oxytetracycline, tetracycline, arsphenamine,chloramphenicol, clindamycin, lincoamycin, ethambutol, fosfomycin,fusidic acid, furazolidone, isoniazid, linezolid, metronidazole,mupirocin, nitrofurantoin, platensimycin, pyrazinamide,quinupristin/dalfopristin, rifampin/rifampicin, timidazole, miconazole,ketoconazole, clotrimazole, econazole, bifonazole, butoconazole,fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole,tioconazole, fluconazole, itraconazole, isavuconazole, ravuconazole,posaconazole, voriconazole, teronazole, terbinafine, amorolfine,naftifine, butenafine, anidulafungin, caspofungin, micafungin,ciclopirox, flucytosine, griseofulvin, Gentian violet, haloprogin,tolnaftate, undecylenic acid, and combinations thereof.

Another embodiment of the disclosure is a method, wherein the targettissue is located in at least one selected from the group consisting ofthe abdominal cavity, cranial cavity, gastrointestinal tract, paranasalsinus, pelvic cavity, reproductive tract, respiratory tract, thoraciccavity and spinal cavity.

Examples of target tissues in these body cavities include tissues of thenose, mouth, throat, ears, eyes, sinus cavities, lungs, stomach, colon,urethra, urinary bladder, uterus, vagina, fallopian tubes and ovaries.It is preferred that the aerosolizer, such as the IA-1C aerosolizer,have a small diameter such as, for example, 0.64 mm which facilitatesaerosol delivery to the cranial cavity, pelvic cavity or spinal cavity.

Another embodiment of the disclosure is a method, wherein the patienthas at least one condition selected from the group consisting of asthma,cancer, chronic obstructive pulmonary disease, cystic fibrosis,dehydration, diabetes, a genetic disorder, hypoxia, infection,inflammatory disease, osteoporosis, pain, Parkinson's disease,respiratory distress syndrome, and trauma.

Another embodiment of the disclosure is a method, wherein the targettissue is located in the lungs.

Another embodiment of the disclosure is a method, wherein theaerosolizer is inserted into an opening in a patient body.

Another embodiment of the disclosure is a method, wherein the opening isan incision in a patient body.

Another aspect of the disclosure is a method of administering achemotherapeutic aerosol to the lungs of a patient comprising providingan apparatus of the disclosure in which the reservoir contains achemotherapeutic agent; placing the aerosolizer adjacent to a targettissue in the lungs of a patient; and operating the apparatus to producea chemotherapeutic aerosol; whereby a chemotherapeutic aerosol isadministered to the lungs of the patient.

In the methods of the disclosure, a chemotherapeutic aerosol may beadministered. Such aerosols may comprise at least one chemotherapeuticagent. Such chemotherapeutic agents include pharmaceutical agents thatkill rapidly dividing cancer cells and include antineoplastic agents.Such chemotherapeutic agents may comprise, for example, small organicmolecules, peptide chains, antibodies, antibody fragments, nanoparticleformulations, siRNA formulations, polynucleotides or combinations ofthese. A chemotherapeutic agent placed in a fluid, such as a liquid, canbe aerosolized to form a liquid aerosol that is a chemotherapeuticaerosol. Alternatively, a chemotherapeutic aerosol can be formed when aliquid is aerosolized into a gas comprising the continuous phase thatcontains a chemotherapeutic agent (such as bis-(2-chloroethyl) sulfide(g)). A chemotherapeutic aerosol may also be formed when a solidchemotherapeutic agent is provided as a particulate or friable materialand aerosolized to form a solid aerosol. Combinations of theseapproaches to form chemotherapeutic aerosols may also be used.

Another embodiment of the disclosure is a method, wherein thechemotherapeutic agent is cisplatin. Thus, one example of achemotherapeutic agent useful in the methods of the disclosure iscisplatin. Other examples, include protein bound paclitaxel preparationssuch as ABRAXANE™, taxol and gemcitibine.

Another embodiment of the disclosure is a method, wherein theaerosolizer is inserted into an incision in a patient body.

For example, extra long catheters can be inserted in an incision orother opening of a patient with the help of specialized equipment andpositioning software to permit biopsies of far deeper locations thanwould otherwise be reachable. The disclosed apparatus and aerosolizermay be narrow enough to go to these deep locations via such extra longcatheters and can also force a dose down a very long tube to saturate alesion with a chemotherapeutic agent directly.

Another embodiment of the disclosure is a method of administering achemotherapeutic aerosol to a patient comprising providing an apparatusof the disclosure; supplying a chemotherapeutic agent to the apparatus;placing the aerosolizer adjacent to a target tissue in the patient; andoperating the apparatus to produce a chemotherapeutic aerosol; whereby achemotherapeutic aerosol is administered to the patient.

Another aspect of the disclosure is an apparatus comprising a reservoirin fluid communication with a pressure generator; a flexible connectionin fluid communication with the pressure generator; and an aerosolizerin fluid communication with the pressure generator.

Pumps are one example, of a pressure generator. A pressurized fluid tankis another example of a pressure generator. A propeller is anotherexample of a pressure generator. A flexible bladder that has beeneither, internally or externally pressurized, is another example of apressure generator. A pressure generator may also apply a vacuum to movea fluid. Those of ordinary skill in the art will readily recognize otherpressure generators.

Another aspect of the disclosure is an apparatus comprising a reservoirin fluid communication with a pressure generator; an aerosolizer influid communication with the pressure generator; and an extensionattached to the aerosolizer.

Another embodiment of the disclosure is an apparatus, wherein theextension comprises at least one selected from the group consisting of alaminate, a fiber reinforced polymer, a metal, a metal alloy and apolymer.

Another embodiment of the disclosure is an apparatus, wherein theextension comprises a polyether ether ketone.

Another embodiment of the disclosure is an apparatus, wherein theextension comprises a sensor.

Another aspect of the disclosure is a method of administering achemotherapeutic aerosol to a patient comprising providing an apparatusof the disclosure; supplying a chemotherapeutic agent to the apparatus;placing an extension adjacent to a target tissue in the patient; andoperating the apparatus to produce a chemotherapeutic aerosol; whereby achemotherapeutic aerosol is administered to the patient.

Another embodiment of the disclosure is a method, wherein the extensionis inserted into an opening in a patient body.

The apparatus and methods of the disclosure may also be used with drypowder sprayers to produce, or administer, solid aerosols to a targettissue or other surface. The methods of the disclosure may also beperformed using any apparatus disclosed herein.

Although the apparatus and methods have been described in connectionwith specific forms thereof, it will be appreciated that a wide varietyof equivalents may be substituted for the specified elements describedherein without departing from the spirit and scope of this disclosure asdescribed in the appended claims.

What is claimed is:
 1. A method of delivering aerosolized liquid to alocation, comprising: providing an aerosolizer in fluid communicationwith a reservoir, said aerosolizer comprising an elongated sleeve memberwith a proximal end and a distal end, and including at the distal end aninsert having an outer surface with a substantially helical channelsurrounding the outer surface, and an orifice at an end wall thereof;locating the orifice at the location; providing in the reservoir aliquid to be aerosolized; pressurizing liquid flowing from the reservoirto the orifice without exposing the pressurized liquid to gas until itexits the orifice; and passing the pressurized liquid through thehelical channel and through the orifice, thereby aerosolizing thepressurized liquid as it encounters ambient air at a pressure lower thana pressure of the pressurized liquid.
 2. The method of claim 1, whereinthe location is a target tissue of a patient, and further comprising thestep of: placing the orifice of the aerosolizer adjacent to the targettissue prior to the step of passing the pressurized liquid through thehelical channel and through the orifice.
 3. The method of claim 2,wherein the target tissue is located in at least one selected from thegroup consisting of the abdominal cavity, cranial cavity,gastrointestinal tract, paranasal sinus, pelvic cavity, reproductivetract, respiratory tract, thoracic cavity and spinal cavity.
 4. Themethod of claim 2, wherein the patient has at least one conditionselected from the group consisting of asthma, cancer, chronicobstructive pulmonary disease, cystic fibrosis, dehydration, diabetes, agenetic disorder, hypoxia, infection, inflammatory disease,osteoporosis, pain, Parkinson's disease, respiratory distress syndrome,and trauma.
 5. The method of claim 2, wherein the target tissue islocated in the lungs.
 6. The method of claim 2, wherein the aerosolizeris inserted into an opening in a patient body.
 7. The method of claim 6,wherein the opening is a breathing orifice of the patient body.
 8. Themethod of claim 7, wherein the breathing orifice comprises a trachea. 9.The method of claim 6, wherein the opening is a non-breathing orifice ofthe patient body.
 10. The method of claim 6, wherein the opening is anincision in the patient body.
 11. The method of claim 1, furthercomprising the steps of: providing a chemotherapeutic agent in thereservoir; placing the aerosolizer adjacent to a target tissue in lungsof a patient; and operating the aerosolizer to produce achemotherapeutic aerosol; whereby a chemotherapeutic aerosol isadministered to the lungs of the patient.
 12. The method of claim 11,wherein the chemotherapeutic agent is cisplatin.
 13. The method of claim1, wherein the step of passing the pressurized liquid through thehelical channel and through the orifice is performed so that acontinuous flow of a predetermined dose of the aerosolized liquid ispassed through the orifice.
 14. The method of claim 1, wherein the stepof passing the pressurized liquid through the helical channel andthrough the orifice is performed so that discrete bursts of apredetermined dose of the aerosolized liquid are passed through theorifice.